Targeted nutritional strategies in postoperative care
Article information
Abstract
Immunonutrition, which uses specific nutrients to modulate the immune response, has emerged as a vital adjunct to perioperative care. Surgery-induced stress triggers immune responses that can lead to complications, such as infections and delayed wound healing. Traditional nutritional support often overlooks the immunological needs of surgical patients. Immunonutrition addresses this oversight by providing key nutrients, such as arginine, omega-3 fatty acids, glutamine, nucleotides, and antioxidants (vitamins C and E) to enhance immune function and support tissue repair. This review examined the efficacy and safety of immunonutrition in surgical settings, guided by the recommendations of the American Society for Parenteral and Enteral Nutrition and the European Society for Clinical Nutrition and Metabolism. Both organizations recommend immunonutrition for high-risk or malnourished patients undergoing major surgery and support its use in reducing complications and improving recovery. The key nutrients in immunonutrition aim to improve immune cell function, reduce inflammation, and enhance wound healing. Clinical studies and meta-analyses have demonstrated that immunonutrition lowers the infection rate, shortens the length of hospital stay, and accelerates recovery. Challenges hindering the clinical application of immunonutrition include cost, logistics, and a lack of standardized and personalized protocols. Future studies should focus on biomarker-driven approaches, pharmacogenomics, and innovative nutrient formulations. Addressing these issues will help to integrate immunonutrition into clinical practice, ultimately improving surgical outcomes and patient recovery.
INTRODUCTION
Immunonutrition, a specialized dietary approach aimed at modulating the immune response, has emerged as a promising adjunctive therapy in perioperative care [1,2]. Physiological stress induced by surgery elicits a cascade of immune responses, predisposing patients to complications, such as infections and delayed wound healing [3]. Although traditional nutritional support strategies predominantly focus on caloric requirements, they often neglect the specific immunological needs of surgical patients.
Understanding the intricate interplay between nutrition and immune functions is crucial for anesthesiologists in postoperative care units and operating rooms. Immunonutrition offers a tailored approach by providing key nutrients that modulate immune responses and support tissue repair. Immunonutrients, such as amino acids (arginine and glutamine), omega-3 fatty acids (FAs), nucleotides, and antioxidants play pivotal roles in these processes. These nutrients are instrumental in modulating inflammatory responses, boosting immune function, and promoting effective tissue repair, thereby improving perioperative outcomes [4,5].
This review aimed to evaluate the efficacy and safety of immunonutrition in surgical settings, offering insights relevant to anesthesiologists involved in all stages of patient care. Drawing from guidelines established by the American Society for Parenteral and Enteral Nutrition (ASPEN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), this review aimed to provide a comprehensive overview of the current state of immunonutrition in perioperative care. The ASPEN guidelines emphasize the importance of perioperative nutrition in reducing complications and improving recovery. They recommend considering immunonutrition in patients undergoing major surgery, particularly those at a high risk of complications or those with preexisting malnutrition [6]. Similarly, the ESPEN guidelines highlight the role of immunonutrition in modulating the inflammatory response to surgery and promoting wound healing. These guidelines provide valuable recommendations for clinical practice in Europe and other regions [7].
Considering the increasing recognition of the importance of immune modulation in surgical patients, understanding the role of immunonutrition is essential for anesthesiologists. By addressing the specific immunological needs of surgical patients, immunonutrition can potentially improve outcomes and reduce the burden of postoperative complications.
STUDY DESIGN
This study aimed to evaluate the effects of immunonutrition on perioperative outcomes. A comprehensive literature search was conducted using the ScienceDirect and PubMed databases to identify relevant studies and references for this review. To draft and refine this manuscript, we used ChatGPT, a language model developed by OpenAI, to generate and edit the text.
LITERATURE REVIEW
History and development of immunonutrition
Immunonutrition, the practice of modulating the immune system through specific nutritional interventions, has significantly evolved over the past few decades. The concept emerged from the realization that malnutrition and nutrient deficiency severely compromise immune functions, increase susceptibility to infections, and lead to poor clinical outcomes [1,6]. Research in the 1980s and the 1990s identified key nutrients that could enhance immune responses and improve patient outcomes, particularly in patients with critical illnesses and those undergoing surgery [8,9].
The development of immunonutrition has gained momentum with the introduction of specialized nutritional formulations designed to support immune function. These formulas typically include nutrients, such as arginine, omega-3 FAs, nucleotides, and glutamine. Clinical trials conducted in the 2000s provided evidence that immunonutrition can reduce infection rates, decrease the length of hospital stay, and improve recovery in surgical and critically ill patients [10-12]. Consequently, immunonutrition has become an integral part of surgical protocols that aim at optimizing perioperative care and outcomes [1].
Basic concepts and mechanisms of immunonutrition
Immunonutrition is based on the principle that specific nutrients can modulate the function of the immune system, enhance its ability to combat infections, reduce inflammation, and promote healing. Fig. 1 shows that the underlying mechanism of immunonutrition is multifaceted and involves several biological processes.
Key nutrients in immunonutrition
1. Arginine
Arginine is a semi-essential amino acid whose requirements increase significantly under stress-inducing conditions such as surgery or trauma. Arginine is critical for immune function, particularly as a key substrate for T lymphocytes. Its availability directly influences T lymphocyte proliferation and reduces the risk of infection [13]. Arginine is a precursor of nitric oxide (NO), which is synthesized by nitric oxide synthase (NOS). NO activates soluble guanylate cyclase in smooth muscle cells, leading to the conversion of guanosine triphosphate to cyclic guanosine monophosphate. This process activates protein kinase G, which decreases intracellular calcium concentrations and induces smooth muscle relaxation through various signaling pathways, resulting in vasodilation. The resulting increase in blood flow enhances tissue oxygenation and vascular permeability [14]. The vasodilatory effects of NO also facilitate greater oxygen delivery, promote leukocyte infiltration, and enhance the microbicidal activity of macrophages [15,16]. In addition to its role in immune functions, arginine is a precursor of proline. Proline is crucial for the synthesis of hydroxyproline, a major component of collagen, essential for proper wound healing. Arginine is metabolized by arginase-1 in the kidneys to produce ornithine and urea, which are subsequently converted to proline, which in turn, undergoes hydroxylation to form hydroxyproline [17-19]. Deficiency in arginine, and consequently NO production, has been implicated in delayed wound healing [20]. Furthermore, arginine deficiency is associated with impaired microperfusion, decreased immune function, and a higher risk of ischemia due to endothelial dysfunction [21].
2. Omega-3 FAs
Omega-3 FAs are polyunsaturated FAs (PUFAs), including alpha-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Omega-3 FAs are essential FAs that cannot be synthesized endogenously and must be acquired from dietary sources, predominantly from cold-water fatty fish. They are key components of cell membranes and act as precursors to bioactive molecules, such as prostaglandins, thromboxanes, and leukotrienes, which contribute to immune regulation and exhibit significant anti-inflammatory properties [22-24]. In particular, EPA and DHA attenuate the production of proinflammatory cytokines and eicosanoids derived from arachidonic acid, an omega-6 FA. Additionally, they enhance the synthesis of resolvins and protectins, which are involved in resolving inflammation, and thus, contribute to wound-healing processes [25-27]. Omega-3 FAs also possess antithrombotic properties, help maintain tissue microperfusion, and stimulate the production of prostaglandin E2. These contribute to preventing immunosuppression at the cellular level [28]. Consequently, omega-3 FA supplementation is recommended for conditions characterized by heightened inflammatory responses, such as surgical procedures [29,30].
3. Nucleotides
Nucleotides, which are fundamental components of deoxyribonucleic acid and ribonucleic acid, are nitrogen-based molecules involved in nearly all intracellular processes [31]. Although nucleotides are synthesized endogenously, they are also obtained through dietary intake of proteins found in animal and plant cells [32]. Nucleotides play a critical role in enhancing immune function by supporting the differentiation and proliferation of T lymphocytes. These processes are particularly important during surgery or infection when the demand for immune cell production and tissue regeneration increases [31,33]. Thus, the nucleotide requirement is markedly increased during surgery or infection [34].
4. Glutamine
Glutamine is a conditionally essential amino acid and the most abundant amino acid in the body, accounting for the highest concentration of all amino acids in the plasma [35]. Under catabolic conditions induced by stress, trauma, or surgery, the demand for glutamine increases, because it serves as the primary energy source for the kidneys, intestinal mucosa, and immune cells [36]. Previous studies have reported that plasma glutamine levels significantly decline in patients with burns, major surgeries, trauma, or critical illness [37,38]. In these patients, glutamine depletion leads to impaired intestinal cell function and a subsequent decline in immune function.
5. Antioxidants (vitamins C and E)
Antioxidants, such as vitamins C and E, are vital for protecting immune cells from oxidative stress. Vitamin C is a water-soluble vitamin that functions as an antioxidant by neutralizing reactive oxygen species and inhibiting oxidative stress, thereby protecting cellular tissues from damage [39,40]. Vitamin E, the most potent lipid-soluble antioxidant, plays a key role in maintaining cell membrane stability by preventing free radical-induced oxidation of PUFAs within the cell membrane [41,42]. Oxidative stress is a significant issue in postoperative patients because excessive production of free radicals can lead to tissue damage and impede healing [43]. These antioxidant supplements have been shown to reduce organ failure and the length of intensive care unit (ICU) stay, thereby improving recovery outcomes in critically ill patients who have undergone surgery [44].
CLINICAL STUDIES AND EVIDENCE
Review of major clinical studies: results from meta-analyses and systematic reviews
Omega-3 FAs
A meta-analysis reported that continuous administration of omega-3 FAs during both the preoperative and postoperative periods in patients undergoing liver surgery was significantly more effective in reducing postoperative infection rates than the administration of omega-3 FAs during either the preoperative or postoperative period alone. However, no benefits were observed concerning mortality or ileus [45]. A randomized controlled trial (RCT) investigating patients undergoing hepatectomy found that the administration of omega-3 FAs was associated with the amelioration of complications and shortening of the length of hospital stay [46]. In contrast, a systematic review found insufficient evidence to support the preoperative use of omega-3 FAs in patients undergoing major gastrointestinal surgery [47]. Various meta-analyses have reported that the doses of omega-3 FAs provided through enteral or parenteral routes ranged from 2.0–6.5 g per day, which yields a reduction in inflammation-related markers. However, when omega-3 FAs were administered preoperatively to patients undergoing abdominal surgery, no significant effects on inflammatory markers were observed. This outcome may be attributed to the small number of studies, limiting result interpretations [48]. According to another systematic review and meta-analysis, immunomodulatory supplementation of omega-3 and omega-6 FAs, along with antioxidants delivered through enteral nutrition (EN), in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) elicited no significant differences in ICU length of stay (LOS), organ failure, or hospital stay compared with patients administered the standard formula [49,50].
1. Nucleotides
Although studies focusing solely on nucleotide supplementation in humans are limited, animal studies have demonstrated that long-term feeding of a nucleotide-free diet leads to a reduced antibody response to T cell-dependent antigens in rodents. Restoration of nucleotides in the diet results in a rapid improvement in immune function [51,52]. Animal studies have demonstrated that nucleotide supplementation increases jejunal villus height. In human infant models, nucleotide-enriched formulas were found to improve intestinal blood flow, potentially contributing to the preservation of gut barrier integrity [53-55]. However, most studies have combined nucleotides with other immunonutrients such as omega-3 FAs and arginine, resulting in positive outcomes such as reduced infection rates. Therefore, it is difficult to attribute these results solely to the effects of nucleotides [56].
2. Glutamine
Previous small-scale studies in critically ill patients have suggested that glutamine supplementation exerts positive effects by improving immune function and suppressing inflammatory responses [57]. Research in this field has increased substantially over the past decade. While some single-center studies have reported positive outcomes, multicenter trials have demonstrated the negative effects of glutamine supplementation [58]. In one of the largest studies, the Scottish Intensive Care Glutamine or SeleNium Evaluative Trial, a double-blind RCT involving 502 critically ill patients, 20.2 g/day of glutamine was administered via parenteral nutrition (PN). The study revealed that glutamine did not have a significant effect on infection incidence or mortality rate [59]. Similarly, the Reducing Deaths due to Oxidative Stress trial (REDOX), a randomized, blinded trial involving 1,223 patients with multi-organ failure across 40 ICUs in Canada, the United States, and Europe, found that glutamine supplementation was associated with increased mortality without other clinical benefits. It is important to note that the patient population in the REDOX trial consisted of critically ill individuals with multiorgan failure, many of whom received less than 50% of their nutritional requirements via enteral feeding. This limitation affected the interpretation of the findings [60]. Although this was a large-scale study, the condition of the patient population and inadequate nutritional support impeded definitive conclusions. Therefore, additional studies and meta-analyses have been conducted. Although the evidence remains limited, glutamine supplementation has shown some benefits in reducing infection rates and hospital LOS, albeit without any effect on mortality. PN appears to yield more favorable outcomes; however, the optimal dosage and duration of supplementation have yet to be clearly established [61].
A meta-analysis of studies evaluating formulas containing various immunonutrients, including arginine and fish oil, administered to high-risk patients undergoing elective surgery during the preoperative and postoperative periods found a significant reduction in infection rates and LOS, albeit without a difference in mortality [62]. Another meta-analysis of patients undergoing elective gastrointestinal surgery demonstrated that the use of immunomodulatory formulae during the perioperative and postoperative periods led to a reduction in infectious complications, shortened hospital LOS, and decreased overall complications [63]. These findings suggest potential benefits for reducing overall morbidity.
Role of immunonutrition in perioperative recovery
Surgical stress amplifies postoperative inflammatory responses, which can compromise immune function and increase the susceptibility to infections. This stress may also accelerate the depletion of critical nutrients involved in immune regulation, potentially leading to deficiencies [64]. In a prospective randomized study, perioperative immunonutrition was administered to patients undergoing pancreaticoduodenectomy, which yielded positive effects on key immunological parameters, including T helper type 1 (Th1), Th2 cells, and interleukin (IL)-17-producing CD4(+) helper T (Th17) cells. Additionally, reductions in postoperative infectious complications and immunosuppression were observed [65]. Another study focusing on patients with a low skeletal muscle index undergoing pancreaticoduodenectomy found that preoperative immunonutritional supplementation suppressed IL-6 levels, which correlated with a reduction in postoperative complications [66]. A meta-analysis of patients undergoing pancreaticoduodenectomy demonstrated that perioperative immunonutrition, provided both before and after surgery, was more effective in reducing infectious complications than immunonutrition provided either preoperatively or postoperatively [67]. A meta-analysis of seven RCTs that enrolled patients undergoing gastrointestinal surgery revealed that preoperative immunonutrition reduced the rate of infectious complications by nearly 50% compared with that in the control group. Additionally, the average length of hospital stay was significantly shortened, from 15.3 days in the control group to 13.6 days in the immunonutrition group [68].
A meta-analysis of 24 studies involving patients undergoing head and neck or gastrointestinal cancer surgery further confirmed that immunonutrition significantly ameliorated all postoperative complications [69]. Meta-analyses of multiple RCTs investigating patients with gastric and colorectal cancers demonstrated a reduction in infectious complications with the use of immunonutrition [70,71].
An observational, retrospective cohort study of patients undergoing gastrectomy who received nutritional support for an average of 10 days pre- and postoperatively also showed that immunonutrition significantly shortened the hospital stay by 34% and reduced infectious complications by 70.1% [72]. Although variations in study scale and outcome measures hinder the drawing of definitive conclusions on perioperative immunonutrition, it can be inferred that immunonutrition plays a crucial role in alleviating surgery-induced inflammatory responses and immune suppression, potentially reducing infectious complications and shortening the length of hospital stay.
PRACTICAL APPLICATIONS AND RECOMMENDATIONS
Guidelines for the use of immunonutritional supplements
Although arginine has been shown to positively influence immune function and wound healing, its supplementation remains controversial, and caution is advised when administering it to patients with septic shock [6]. Inflammatory stimuli can activate inducible NOS, an intracellular enzyme that converts arginine to NO, leading to vasodilation. This can result in hemodynamic instability and tissue damage, necessitating careful consideration when administering arginine to this patient population [21].
Glutamine supplementation is not recommended for all patients except those with trauma or burns. In critically ill patients with complex conditions, especially those with liver or renal failure, the use of glutamine via PN is not advised [73].
The SCCM/ASPEN guidelines do not recommend routine administration of formulas containing omega-3 FAs in patients with ALI or ARDS, as shown in Table 1. However, immunomodulatory formulas containing arginine and fish oil are recommended postoperatively for patients admitted to the surgical ICU [6].
Pre- and postoperative immunonutrition management protocols
The ESPEN guidelines recommend the use of immunonutrients (arginine, omega-3 FAs, and nucleotides) during the perioperative period, or at least in the postoperative period, for malnourished patients scheduled for major surgery [7]. In contrast, the American Society for Enhanced Recovery guidelines recommend high-protein oral supplements before major surgery and suggest immunonutritional use [74]. However, evidence supporting the use of immunonutrition remains ambiguous, necessitating large-scale multicenter clinical trials to establish clear guidelines. The current lack of robust evidence hinders the development of standardized protocols, resulting in challenges for consistent implementation in clinical practice.
Clinical application
1. Arginine
The recommended dose of arginine for healthy individuals ranges from 5 to 30 g/day. Commercially available enteral formulas used for immune support in critically ill patients typically contain arginine at concentrations ranging from 0 and 18.7 g/L. In contrast, domestic enteral formulas contain significantly lower arginine levels ranging from 0 to 5 g/L. International clinical studies have reported that critically ill patients who achieve their target nutritional intake via enteral feeding receive an average arginine dose of 10–30 g/day [75]. For perioperative or critically ill patients, determining the exact dose can be challenging because of metabolic instability and inflammatory states. However, arginine supplementation should remain within the 10–30 g/day range, because higher doses may increase the risk of adverse effects [6,15].
2. Omega-3
While it remains challenging to accurately delineate the therapeutic effect and no specific recommended dosage has been established, the omega-3 FA content in currently available enteral formulas in South Korea ranges from 0.8 to 1.7 g/L. Commercially available 20% lipid emulsion solutions contain approximately 3 g of fish oil per 100 ml, accounting for approximately 15% of the total volume. In lipid-based PN formulations, the composition of FAs varies according to the manufacturer; however, fish oil-based preparations typically comprise 15–20% of the total lipid content. According to the Dietary Guidelines for Americans 2015–2020, the recommended daily intake of omega-3 FAs to maintain optimal physiological function is 450–500 mg/day [76]. According to the Dietary Reference Intakes for Koreans 2020, the adequate intake of omega-3 FAs for adults aged 50–64 years is set at 500 mg/day for men and 240 mg/day for women [77].
3. Nucleotides
The exact nucleotide content of individual food items has not been officially established; however, it is estimated that healthy individuals consume approximately 1–2 g/day through their diet. Some commercially available enteral formulas from international sources contain between 1.2 and 2.8 g/L of nucleotides [56]. However, the nucleotide content of domestic Korean products is yet to be determined.
4. Glutamine
The recent ESPEN guidelines recommend the administration of glutamine via EN for trauma patients at a dose of 0.2–0.3 g/kg/day for the first 5 days of initiating EN. In cases of complicated wound healing, glutamine should be administered for more than 10–15 days, and for patients with burns with body surface area involvement exceeding 20%, the recommended dosage is 0.3–0.5 g/kg/day for 10–15 days. Glutamine supplementation is not recommended in patients other than those with trauma or burns. Additionally, for critically ill patients with complex conditions, particularly those with liver or renal failure, the use of glutamine via PN is not advised [73].
5. Vitamin C and E
The 2020 Korean Dietary Reference Intake guideline recommends a daily intake of 100 mg vitamin C, a water-soluble vitamin, while the adequate intake for vitamin E, a fat-soluble vitamin, is 12 mg α-TE per day [77]. Among the commercial EN products available in Korea, the vitamin C content ranges from 140 mg to 500 mg per 1,000 kcal, and the vitamin E content ranges from 10 mg to 50 mg α-TE per 1,000 kcal.
As shown in Table 2, none of the domestically available EN formulas contain glutamine or nucleotides. Moreover, glutamine is only available as an intravenous preparation. Currently, the EN formulas available in Korea do not provide all immunonutrients in a single product. Among the formulations commonly used for the immune support of critically ill patients, some include omega-3 FAs, such as DHA and EPA. However, arginine, which should be restricted in cases of sepsis, is not included [6].
Challenges and considerations
The clinical application of faces several significant hurdles. Identifying and addressing the various obstacles that hinder the widespread application of immunonutrition is crucial. One of the primary concerns is the substantial cost of immunonutritional supplements. These costs may limit access for some patients and healthcare facilities, particularly those operating under tight budget constraints [78].
Logistical constraints pose significant challenges. Ensuring the timely and appropriate delivery of immunonutritional supplements is a complex task, especially in busy clinical settings. This complexity is compounded by a lack of standardized protocols, which leads to variability in the administration and effectiveness of immunonutrition. In the absence of clear guidelines, healthcare providers may struggle to implement these strategies consistently and effectively [1].
Personalized approaches to immunonutrition are essential for optimizing patient outcomes. Individual patient characteristics, such as nutritional status, comorbidities, and specific types of surgery should inform tailored nutritional interventions [79]. Standardized protocols alone cannot address the unique needs of each patient, highlighting the importance of personalized nutritional plans.
In summary, although immunonutrition holds great promise for improving surgical outcomes, its implementation is challenging. Addressing cost and logistic issues, developing standardized protocols, and emphasizing personalized approaches based on patient characteristics and surgical procedures are critical steps toward overcoming these obstacles and realizing the full potential of immunonutrition in clinical practice.
FUTURE DIRECTIONS
Immunonutrition use in surgical patients is poised for significant advancements driven by emerging research and technological innovations. A promising research area is the development of biomarker-driven approaches. By identifying specific biomarkers associated with nutritional status and the immune response, clinicians can tailor immunonutritional interventions to the individual needs of patients, thereby enhancing their efficacy and outcomes [80,81]. These biomarkers can help predict patients who are most likely to benefit from specific nutrients, thereby enabling more personalized and effective treatment plans.
Pharmacogenomics, the study of how genes affect an individual’s response to drugs, offers exciting possibilities for immunonutrition. By understanding the genetic variations that influence nutrient metabolism and immune function, personalized nutrition plans can be developed to optimize the immune modulations and recovery of each individual surgical patient [80,82,83]. This approach ensures that patients receive the most suitable nutrients in the correct amounts based on their genetic profiles, thus, potentially improving surgical outcomes and reducing complications.
Innovations in the formulation and delivery of immuno-nutritional supplements constitute another key area for future research. Novel formulations that enhance the bioavailability and stability of key nutrients could improve their effectiveness. Moreover, advanced delivery methods, such as encapsulation technologies and targeted delivery systems, can ensure that nutrients are delivered precisely where they are needed, maximizing their therapeutic potential [84,85].
To fully realize the potential of immunonutrition, it is essential to conduct multicenter RCTs with standardized protocols. These trials can provide robust evidence of the efficacy of immunonutrition in various surgical populations and help clarify the role of specific nutrients in improving surgical outcomes. Additionally, standardized protocols are needed to ensure consistency and reliability in administering immunonutritional interventions and may facilitate better comparisons of results across different studies.
By integrating these advancements, the field of immunonutrition can move towards more personalized, effective, and evidence-based practices, ultimately enhancing the recovery and overall health of surgical patients.
CONCLUSION
Immunonutrition plays a crucial role in optimizing surgical outcomes by enhancing immune functions, reducing inflammation, and promoting wound healing. Despite its potential, the implementation of immunonutrition faces significant challenges including cost, logistical constraints, and the lack of standardized protocols. Further research is essential to overcome these obstacles and validate the efficacy of tailored nutritional interventions. Continued efforts to refine immunonutritional strategies are necessary to improve perioperative care and optimize patient recovery following surgery. By addressing these challenges, the full potential of immunonutrition may be realized, ultimately benefiting the patient’s health and surgical success.
Notes
FUNDING
None.
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
DATA AVAILABILITY STATEMENT
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
AUTHOR CONTRIBUTIONS
Writing - original draft: Jeongmin Kim. Writing - review & editing: Hye Jin Ham, Jeongmin Kim. Conceptualization: Jeongmin Kim. Formal analysis: Jeongmin Kim. Methodology: Jeongmin Kim. Visualization: Jeongmin Kim. Investigation:Jeongmin Kim. Validation: Jeongmin Kim.